BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] The present invention relates to controlled release oral delivery systems for drugs
such as therapeutic agents and pharmaceuticals. More particularly, the present invention
relates to polymeric swelling-controlled drug release formulations for delivery of
drugs to a point beyond the stomach such as to the small intestine or colon. The subject
formulations are particularly suitable for delivery of therapeutic agents which are
normally destroyed by gastric juices in the gastrointestinal tract, or which cause
gastric irritation. The subject formulations comprise a cross-linked polyacid resin
having a selected drug imbibed or entrapped therein and are characterized in that
they swell minimally in a gastric environment with no significant loss of drug and
swell extensively, while remaining insoluble, in an environment having a pH value
greater than that of the gastric environment, such as in an intestinal environment,
to release an effective amount of the drug therein.
2. Description of Related Art
[0002] Enteral or oral administration of drugs is the most common method of administration,
generally because it is the safest, most convenient and most economical. However,
not all drugs are suitable for enteral administration. For example, drugs that are
destroyed by gastric juices, such as insulin, or that cause gastric irritation, such
as aspirin, are administered, respectively, by parenteral injection or in dosage
forms with a coating that controls dissolution in the acidic gastric contents.
[0003] Controlled release of therapeutic agents is dependent upon the dissolution rate of
the coating which is sometimes irregular because of variations in gastrointestinal
pH, gastric emptying and other physiological factors. Moreover, absorption from the
gastrointestinal tract is often incomplete and erratic.
[0004] Parenteral injection of drugs, particularly on a day-to-day basis, also has disadvantages
associated therewith. Unfavorable reactions are prone to occur due to high concentrations
of drugs which are attained rapidly in both plasma and tissues. Furthermore, repeated
intravenous injections are dependent upon the ability to maintain a patent vein.
[0005] Therefore, it is preferable, when possible, to administer drugs enterally. To this
end, many attempts have been made at developing drug delivery systems for enteral
administration of drugs which, historically, have been administered parenterally or
are known to cause gastric irritation.
[0006] One such attempt is described in U.S. Patent No. 4,663,308 wherein azo polymers are
utilized to provide delivery of drugs to or through the mucosa of the large intestine.
The drug is coated with a polymer of ethylenically unsaturated monomers cross-linked
by a divinylazobenzene composition. The azo bonds are said to be stable to digestive
juices in the mouth, stomach or small intestine and subject to degradation, by azo
reductases existing in the large intestine. Once the polymer coating begins to degrade,
the drug is released into the large intestine where, depending upon the specific therapeutic
action of the drug, it either is absorbed through the mucosa of the large intestine
or begins to act at that location.
[0007] Other attempts include those described in U.S. Patent Nos. 4,575,539 and 4,423,099
and references cited therein which utilize polymeric materials to form hydrogels
(pH-independent, water-swellable, cross-linked polymers based primarily on 2-hydroxyethylmethacrylate).
However, hydrogels typically swell under gastric conditions and thereby release a
significant amount of drug in the stomach.
[0008] Swelling-controlled release systems are relatively new devices of the controlled
release family of delivery devices for applications in pharmaceutical technology.
To date, emphasis has been placed on swelling-controlled systems for release of a
drug at a constant rate over a period of time (zero-order systems). Such systems are
discussed by R. W. Korsmeyer and N. A. Peppas in
Controlled Release Delivery Systems, Edited by T. J. Roseman and S. Z. Mansdorf, Chapter 4, pp. 77-90, Marcel Dekker,
Inc. Publishers (1983). Specific systems are noted at pp. 87-89. Although no successful
pharmaceutical formulation of this type "is yet known in the literature", it is suggested
that possible modifications of the solubility of the polymer may lead to a desirable
formulation.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention resides in the discovery that cross-linked polyacid resins
having swelling characteristics which are pH-dependent are particularly suited for
formulating swelling-controlled systems for site-specific delivery of drugs to those
portions of the gastrointestinal tract which are beyond the stomach and at higher
pH values. The subject invention is particularly useful for delivery of relatively
high molecular weight protein and polypeptide drugs or therapeutic agents through
the stomach and to the small intestine.
[0010] The present polymeric formulations include cross-linked polyacid resins which have
a selected drug imbibed or entrapped therein. As utilized herein, thereapeutic agent,
drug and pharmaceutical are synonomous. These formulations manifest minimal swelling
in a gastric environment, i.e., the amount of therapeutic agent lost due to release
by swelling is insignificant, typically less than about 25% by weight, at a pH of
from about 1 to about 6. Furthermore, once past the stomach and in an environment
having a higher pH value, i.e., at a pH of from about 6 or greater, such formulations
manifest extensive swelling, i.e., to an extent sufficient to release an effective
amount of a therapeutic agent therein, for example, into the small intestine, where,
depending upon the specific therapeutic action of the agent, it either is absorbed
through the mucosa of the small intestine or begins to act therein. It is postulated
that swelling of the present formulation in environments at pH values greater than
about 6 is due to polyanion formation therein. For example, it is postulated that
swelling of the present formulation in the small intestine is due to polyanion formation
of the polyacid with bicarbonates secreted from the pancreas.
[0011] The subject formulations are particularly effective where the therapeutic agent is
a relatively high molecular weight protein or polypeptide, for example, insulin. Although
"conventional wisdom" teaches that peptides and proteins cannot readily pass through
the wall of the intestine
(For example, see Oral Delivery of Polypeptides: Identifying and Overcoming the Rate
Limiting Mechanisms of Degradation and Transport, Proc. Intern. Sypm. Control. Rel. Bioact. Mater. 15, No. 39, pp. 60-61 (1988), Controlled
Release Society, Inc.), it is believed that such observation is derived from the improbability
of an orally delivered peptide or protein being delivered to the intestinal wall without
first being denatured or degraded by gastric pepsin, or by one or more of various
proteases, encountered in the duodenal portion of the small intestine. Once a protein
is fragmented by these enzymes, these fragments will then be further degraded by peptidases
which are in high concentration in the cellular wall of the small intestine. however,
the present polymeric swelling-controlled oral delivery system protects such polypeptides
while moving through the stomach and duodenum so that degradation by gastric pepsin
or a protease does not readily occur.
DETAILED DESCRIPTION
[0012] The polymeric swelling-controlled drug delivery systems of the present invention
comprise cross-linked insoluble polyacid resins having a therapeutic agent imbibed
therein. These formulations are prepared by imbibing a solution of the therapeutic
agent into the cross-linked polyacid resin with subsequent removal of solvent.
[0013] Suitable polyacid resins include resins of polycarboxylic acids such as homopolymers
and copolymers comprising carboxylic acid monomers having up to about four carbon
atoms per carboxylic acid radical, preferably up to about three carbon atoms per carboxylic
acid radical. Examples of such monomers include substituted and unsubstituted acrylic
acid, methacrylic acid, fumaric acid, maleic acid, itaconic acid and crotonic acid.
Suitable acid monomers also include substituted and unsubstituted sulfonic acid monomers
having characteristics similar to those of the carboxylic acid monomers. Examples
of such sulfonic acid monomers include vinyl sulfonic acid and styrene sulfonic acid.
Preferred monomers are acrylic acid and methacrylic acid. Such monomers can be co-polymerized
with each other or with
alpha-olefins such as ethylene. Examples of such suitable polyacid resins, include poly(acrylic
acid), poly(methacrylic acid), poly(vinyl-sulfonic acid), poly(p-styrenesulfonic acid),
poly(styrene-
co-maleic acid), poly(vinyl methyl ether-
co-maleic acid), poly(acrylic acid-
co-maleic acid), poly(ethylene-
co-maleic acid), poly(acrylic-
co-methacrylic) and the like. Preferred polycarboxylic acids include poly(acrylic acid),
poly(methacrylic acid), poly(vinyl methyl ether-
co-maleic acid), poly(ethylene
co-maleic acid) and poly(acrylic-
co-methacrylic). Particularly preferred resins are poly(acrylic acid) and poly(methacrylic
acid).
[0014] Preparation of such suitable polyacids is accomplished by combining monomer(s), a
cross-linking agent and a polymerization initiator in a substantially salt-free aqueous
solution, and stirring and heating the solution, preferably under a positive nitrogen
pressure sufficient to maintain a nitrogen atmosphere, until polymerization is substantially
complete. After cooling, the resulting gelatinous slurry is poured into an appropriate
container and the solvent is removed, such as in a vacuum oven. Preferably, the resultant
dry resin is then ground in a mill and the portion passing through a 40 mesh screen
(<425µm) is utilized for subsequent drug loading.
[0015] Suitable cross-linking agents include monomers containing at least two vinyl groups.
Examples of such cross-linking agents include butylene diacry late, ethylene di(meth)acrylate,
divinyl benzene, ethylene glycol di(meth)acrylate, di-, tri- and tetraethylene glycol
di(meth)acrylate, methylene bisacrylamide, as well as other conventional cross-linking
agents which will form a cross-linked polymer with the polyacid.
[0016] Suitable polymerization initiators include water soluble peroxy and azo polymerization
initiator compounds. Examples of water soluble peroxy compounds are sodium persulfate
and potassium persulfate. Examples of water soluble azo polymerization initiators
are 2,2′-azobis (N,N-dimethyleneisobutyramide), 4,4′-azobis (4-cyanopentanoic acid),
2,2′-azobis (2-amidino propane) dihydrochloride. A preferred initiator is potassium
persulfate.
[0017] The cross-linking agent is employed in an amount which will render the polyacid completely
insoluble yet not interfere with the swelling characteristics. Suitable amounts are
employed in a weight ratio, of cross-linking agent to carboxylic acid monomer, of
within the range of about 1:1 to about .001:1, and a weight ratio of cross-linking
agent to polymerization initiator of within the range of from about 0.001:1 to about
0.005:1. Preferably the amount of cross-linking agent utilized does not contribute
less than about 0.5 mol % nor more than about 20 mol % of the total monomer mixture.
At levels higher than about 20 mol %, the amount of cross-linking affects and sometimes
impedes absorption of the therapeutic agent into the polymer. It is well within the
skill of one in the art to determine which therapeutic agents are adapted to be absorbed
into a polyacid wherein more than about 20 mol % is cross-linked. At levels lower
than about 0.5 mol % the therapeutic agent is more likely to leach out under gastric
conditions. It is well within the skill of one in the art to determine which therapeutic
agents are adapted to be utilized with polyacids wherein less than about 0.5 mol %
of the polyacid is cross-linked.
[0018] The polymerizations are carried out according to conventional methods except that
they are conducted in salt-free solutions. Conventional methods, such as disclosed
in U.S. Patent No. 3,202,577, utilize a saturated salt solution, such as a saturated
MgSO₄ solution. However, polymers produced according to such methods swell to a much
lesser extent in both gastric and intestinal fluids and, most importantly, significant
amounts of therapeutic agent leach from such resins under gastric conditions. Thus
another aspect of the present invention resides in the discovery that when the polymerizations
of polycarboxylic acids are carried out in the substantial absence of MgSO₄ and other
salts, such polyacids swell only minimally when exposed to gastric conditions without
any significant leaching of the therapeutic agent imbibed therein, yet, when exposed
to conditions of higher pH, such as when exposed to intestinal conditions, swell to
an extent sufficient to release a therapeutic amount of the agent. Such resins are
herein referred to as "salt-free" resins.
[0019] Suitable agents include those which are adapted to be absorbed by the polyacids described
above and which are adapted to be released therefrom, upon swelling, in an amount
sufficient to effect therapeutic action. Preferred therapeutic agents are peptides,
pseudopolypeptides. polypeptides and proteins such as, for example, insulin, glucagon,
parathyroid and pituitary hormones, calcitonin, vasopressin, renin, prolactin, thyroid
stimulating hormone, corticotrophin, follicle stimulating hormone, luteinising hormone,
chorionic gonadotrophin, somatotropins (growth hormones) and the like as well as 5-aminosalicylic
acid (5-ASA). A particularly preferred therapeutic agent is insulin. Another preferred
agent is 5-ASA. The amount of the agent incorporated into the polymer can vary over
a wide range depending on the activity of the agent, the desired effect and other
factors. Preferably, the agent is incorporated in an amount ranging from about 0.1
to about 200 mg agent per gram of polymer, such as from about 20 to about 150.
[0020] The therapeutic agent may be incorporated into the polymer by any technique which
will cause the therapeutic agent to be absorbed into the polymer as opposed to absorbed
onto the surface thereof (which would allow the agent to be released in the stomach).
A preferred technique is to stir the polymer in a non-polar non-solvent and add an
aqueous solution of the therapeutic agent dropwise over a time period of approximately
one minute. Stirring is continued until it appears that the polymer is no longer swelling,
typically from about 30 minutes to about two hours. The polymer/therapeutic agent
matrix is isolated by decanting the organic layer and, where the therapeutic agent
solvent is water, lyophilizing the solid residue. If the therapeutic agent solvent
is non-aqueous, stirring is conducted in air and the solvent may be removed under
vacuum in an oven with or without heat depending on the sensitivity of the drug. The
dried solid is then preferably compacted into tablets utilizing a Parr press or other
conventional tableting equipment known to those skilled in the art. Of course, other
model of enteral delivery may be utilized and any of the known processing steps for
forming such delivery systems may also be utilized.
[0021] The amount of therapeutic agent/polyacid utilized will depend on the particular delivery
system, the desired therapeutic effect, characteristics of both the polyacid and therapeutic
agent, as well as other factors. Thus, optimal amounts of the components and of the
formulations of the present invention can be easily determined by one skilled in the
art.
[0022] When the polymer entrapped therapeutic agent is enterally administered, it passes
through the stomach, with minimal swelling of the polymer and with minimal loss of
therapeutic agent, and into the lower portions of the gastrointestinal tract, such
as to the intestine, where, due to the presence of bicarbonates which are produced
in the pancreas, the pH values are greater than the pH value in the stomach. Upon
exposure to the higher pH values, the polymer begins to swell and thereby releases
an effective amount of the therapeutic agent.
[0023] The following examples are non-limiting illustrative embodiments of the present formulations
and their method of preparation. Variations thereof will be obvious to those skilled
in the art.
EXAMPLE 1
[0024] This example illustrates release of a therapeutic agent from a polymer formulation
of the present invention under simulated gastric and intestinal environments.
[0025] An aqueous solution containing five wt.% monomer, from about 0.5 to about 10 mol%
(based on the monomer), triethylene glycol di(meth)acrylate and one wt.% (based on
the monomer) potassium persulfate were stirred under a positive nitrogen pressure
at 55°C for three hours and 65°C for two additional hours. After cooling, the gelatinous
slurry was poured into an appropriate container and the water removed in a vacuum
oven at 75°C with a nitrogen bleed. The resin was then ground in a mill and the portion
passing through a 40 mesh screen i.e., <425µm, was retained for drug loading according
to the following procedure.
[0026] One gram of the resin was placed in a 50 ml Erlenmeyer flask, covered with 25 ml
hexane and the slurry stirred magnetically. Five ml of an aqueous solution of the
therapeautic agent was added dropwise over a period of about one minute. Stirring
was continued for about one hour. The resin/therapeutic agent mixture was isolated
by decanting the organic layer and lyophilizing the solid residue. The dried solid
was then compacted into tablets utilizing a Parr press.
[0027] A spectroscopic working curve was then developed for varying concentrations of therapeutic
agents in water.
[0028] Two 0.5 gram resin/drug tablets were placed in an Erlenmeyer flask and magnetically
stirred in 50 ml of the synthetic gastric fluid described below (pH∼1). After one
hour, the flask contents were centrifuged and the supernate decanted and assayed for
its drug content.
[0029] The solid was washed into a second flask with 50 ml of the synthetic intestinal fluid
(pH∼7) and 70 ml of the isotonic bicarbonate solution described below (which is sufficient
to neutralize the acid function of the resin resulting in a slurry pH of about 7 to
8). After stirring two hours, the slurry was centrifuged and the supernate was assayed
for released drug by UV at 254nm.
[0030] Results utilizing various polymers, various amounts of cross-linking agent and various
polypeptide therapeutic agents are illustrated in Table 1.
TABLE 1
% EXTRACTION OF IMBIBED AGENTS FROM POLYACID RESINS UNDER SYNTHETIC GASTRIC (1 HR)
FOLLOWED BY INTESTINAL (2 HRS.) CONDITIONS |
|
Human Serum Albumin |
Insulin |
Tyr-Ala Dipeptide |
5-Amino-Salicylic Acid |
|
(50mg/g) |
(50mg/g) |
(40mg/g) |
(40mg/g) |
PROTECTING RESIN |
gast |
int |
gast |
int |
gast |
int |
gast |
int |
Acrylic Acid |
|
|
|
|
|
|
|
|
2% cross-linked |
|
|
0 |
55 |
|
|
|
|
5% cross-linked |
0 |
64 |
10 |
78 |
79 |
10 |
77 |
24 |
10% cross-linked |
|
|
5 |
73 |
|
|
87 |
13 |
Methacrylic Acid |
|
|
|
|
|
|
|
|
3% cross-linked |
|
|
4 |
28 |
|
|
|
|
5% cross-linked |
0 |
75 |
1 |
43 |
10 |
41 |
12 |
64 |
10% cross-linked |
|
|
2 |
31 |
|
|
69 |
31 |
Ethylene/Maleic Anhydride Copolymer |
|
|
|
|
|
|
|
|
5% cross-linked |
0 |
96 |
- |
100 |
92 |
20 |
78 |
32 |
Methyl Vinyl Ether/Maleic Anhydride Copolymer |
|
|
|
|
|
|
|
|
5% cross-linked |
0 |
17 |
2 |
10 |
31 |
36 |
49 |
41 |
EXAMPLE 2
[0031] This example demonstrates the difference between "salt polymerized" resins and those
prepared in the substantial absence of salt, i.e., salt-free resins, according to
the teachings of the present invention.
[0032] Poly(acrylic acid) and poly(methacrylic acid) resins (5 mol % cross-linking) were
prepared as in Example 1 with the polymerizations being carried out in a saturated
MgSO₄ solution. These resins were imbibed with insulin and compared with insulin-imbibed
resins obtained according to the procedure of Example 1 in synthetic gastric and intestinal
fluids. The results, which are presented in Table 2, demonstrate that "salt polymerized"
resins not only swell to a much lesser extent, but also that significant amounts of
insulin are leachable therefrom.
[0033] Swelling was determined by the following procedure. One gram of the resin was placed
in a graduated cylinder and shaken with 25ml of a synthetic gastric fluid (2g NaCl,
7 ml concentrated HCl, diluted to one liter with water). A second one gram portion
was shaken in a graduated cylinder with 50ml of synthetic intestinal fluid (6.8g
NaCl, 5.0g NaH₂PO₄.H₂O, 0.8g Na₂HPO₄.7H₂O, diluted to one liter with water) and 70
ml of an isotonic bicarbonate solution (13.3g NaHCO₃ diluted to one liter with water).
Both test cylinders were allowed to stand overnight and the volume of the settled
resin was recorded.
[0034] The amount of insulin leached after two hours in synthetic gastric fluid was determined
by HPLC according to the following procedure.
INSULIN HPLC SCHEME
[0035] Column: Whatman ODS CSK Guard Colum
Whatman Protesil 300 Octyl, 10um
Solvent A: 0.1% TFA in water
Solvent B: 0.1% TFA in acetonitrile
Gradient: 0-3.6 min, hold 15%B
3.6-4.6 min, linear, 15-32%B
4.6-14 min, linear, 32-41.4%B
14-15 min, linear, 41.4-90%B
15-18 min, hold 90%B
18-19 min, linear, 90-15%B
19-27 min, hold 15%B
Flow Rate: 0-15 min, 1.5 ml/min
15-24 min, 2.5 ml/min
24-27 min, 1.5 ml/min
Detection: UV, 254 nm
Sample: 50 ul
TABLE 2
|
Swelling, ml |
|
Resin |
Gastric |
Intestinal |
Gastric Environment Leached Insulin % |
Acrylic |
|
|
|
Acid(H₂O) |
6 |
30 |
12 |
Acid(MgSO₄) |
4 |
10 |
44 |
Methacrylic |
|
|
|
Acid(H₂O) |
7 |
20 |
24 |
Acid(MgSO₄) |
4 |
7.5 |
64 |
EXAMPLE 3
[0036] This example illustrates that release of therapeutic agents from hydrogel formulations
is not dependent on pH and that such formulations do not inhibit release of such
agent under gastric conditions.
[0037] A hydroxyethyl methacrylate/acrylic acid hydrogel was prepared. Twenty grams of methacrylate
ester and acrylic acid, in a 1:1 molar ratio, were stirred in 300 ml of water containing
0.15 g of potassium persulfate and about 5 mol % (based on the total molar amount
of monomers) triethylene glycol diacrylate, and heated at 95°C for two hours under
nitrogen. Water was then evaporated in an oven at 75°C under vacuum until the polymer
was dry. The hydrogel was then ground in a mill and the portion passing through a
40 mesh screen was retained for drug loading.
[0038] Insulin was added to the hydrogel, according to the procedure set forth in Example
1 for formulating the polyacid resin/therapeutic agent of the present invention,
in an amount to effect samples containing 50 mg of insulin per gram of hydrogel.
[0039] The samples were utilized in simulated gastric and intestinal environments according
to the procedure set forth in Example 1 and assayed, using the HPLC procedure described
in Example 2, to determine the amount of insulin released. Results are reported in
Table 3.
TABLE 3
Time(hrs.) |
pH |
Insulin Released(mg) |
% Release |
0.08 |
1.45 |
24.2 |
48.4 |
0.33 |
1.34 |
37.1 |
74.2 |
0.67 |
1.36 |
39.0 |
78.0 |
1.00 |
1.37 |
40.0 |
80.1 |
1.33 |
1.36 |
40.1 |
80.3 |
1.67 |
1.37 |
40.1 |
80.3 |
2.00 |
1.39 |
39.2 |
78.5 |
0.08 |
7.75 |
22.3 |
44.6 |
0.50 |
7.46 |
30.4 |
60.9 |
1.00 |
7.80 |
32.0 |
64.1 |
2.00 |
7.64 |
35.3 |
70.6 |
3.00 |
7.61 |
37.5 |
75.1 |
4.00 |
7.65 |
38.0 |
76.1 |
EXAMPLE 4
[0040] This example illustrates the effectiveness of the formulations of the present invention
over a range of therapeutic agent loading.
[0041] Formulations were prepared according to the procedure set forth in Example 1 (with
5 mol % cross-linking) and assayed at various pH levels utilizing the HPLC procedure
described in Example 2. Results are reported in Table 4.
TABLE 4
Resin |
Mg Insulin/Gram Resin |
Time (hrs.) |
pH |
Insulin Released(%) |
Poly (Methacrylic Acid) |
50 |
2 |
0.9 |
20.60 |
50 |
2 |
2.8 |
0.02 |
50 |
2 |
5.0 |
0.02 |
50 |
2 |
7.6 |
35.52 |
100 |
2 |
1.11 |
12.76 |
100 |
2 |
4.71 |
1.16 |
100 |
2 |
7.58 |
22.92 |
Polyacrylic Acid |
50 |
2 |
1.23 |
16.33 |
50 |
2 |
4.74 |
2.04 |
50 |
2 |
6.86 |
90.44 |
EXAMPLE 5
[0042] In this example, the efficary in diabetic rats is demonstrated for orally administered
insulin imbibed in a polyanionic resin according to the teachings of the present
invention.
[0043] Powdered resins containing 50 mg of insulin per gram of poly(acrylic acid) and poly(methacrylic
acid) resin were prepared according to the procedures set forth in Example 1. A poly(methacrylic
acid) containing 100 mg of insulin per gram of resin was also prepared utilizing
the procedures of Example 1.
[0044] Rats were treated with 50 mg/kg of streptozotocin (STZ) which renders the rats diabetic
by destroying the pancreatic islets which produce insulin. The urine of the rats
was monitored with "glucose sticks" to assure that there was an increase in glucose
output.
[0045] The rats were allowed to eat and drink freely (ad libidum) and were treated with
18 Units of bovine serum insulin in the polyacid resins twice a day. This was repeated
daily for two weeks. Two hours after the last dose, the rats were sacrificed and their
blood stored (refrigerated) for subsequent assay.
[0046] Group 1-4 (A-50) was treated with poly (acrylic acid) resin containing 50 mg insulin/g
resin. Group 6-10 (M-100) was treated with poly(methacrylic acid) resin containing
100 mg insulin/g resin. Group 16-20 (Gel) was a positive control group treated with
a compounded formulation of
human insulin in gelatin (dissolves in the stomach). Group 21-25 was the neutral control
and did not get
STZ or insulin. Group 27-31 was the negative control and was rendered diabetic but received
no insulin. The results show that in the case of the first formulation, 50 mg insulin
in lg acrylic acid resin, there were 3/4 rats with serum glucose reductions and higher
levels of serum insulin than found for the diabetic, no treatment group. A similar
finding also resulted for 2/4 responding rats treated with the second formulation,
50 mg insulin in lg methacrylic acid resin. The third formulation, 100 mg insulin
in lg methacrylic acid resin, was an ineffective treatment at the same insulin dose
level. The rationale for this lack of activity is that the higher insulin level results
in a more adherent powder that has been shown to have a slower rate of drug release
in
in vitro tests (Example 4).
TABLE 5
|
Rat Number |
% Weight Gained |
Glucose Serum Conc. mg/dL |
Insulin Serum Conc. µU/ml |
Group A-50 |
1 |
50 |
317 |
119 |
2 |
62 |
460 |
77 |
3 |
62 |
171 |
353 |
4 |
59 |
380 |
198 |
Group M-50 |
6 |
55 |
502 |
128 |
7 |
66 |
181 |
133 |
9 |
46 |
476 |
95 |
10 |
63 |
203 |
170 |
Group M-100 |
11 |
36 |
487 |
101 |
12 |
20 |
514 |
113 |
13 |
40 |
447 |
105 |
14 |
34 |
512 |
109 |
15 |
61 |
|
|
Group Non-DIAB No-TREAT |
21 |
81 |
165 |
80 |
22 |
74 |
173 |
-- |
23 |
82 |
178 |
59 |
24 |
81 |
239 |
49 |
25 |
71 |
161 |
73 |
Group DIAB No-TREAT |
27 |
64 |
514 |
27 |
28 |
63 |
-- |
79 |
29 |
57 |
538 |
89 |
30 |
59 |
498 |
39 |
31 |
64 |
433 |
39 |
1. Swelling-controlled drug delivery system for enteral administration of a therapeutic
agent comprising a therapeutic agent imbibed in a polyacid resin adapted to swell
minimally in a gastric environment with no significant loss of said therapeutic agent,
and swell extensively while remaining insoluble in an environment having a pH value
greater than that of the gastric environment with release of an effective amount
of said therapeutic agent.
2. Drug delivery system of Claim 1 wherein said polyacid resin is a salt-free resin.
3. Drug delivery system of Claim 2 wherein said polyacid resin is selected from the
group consisting of poly(acrylic acid), poly(methacrylic acid), poly(vinyl sulfonic
acid), poly(p-styrene sulfonic acid), poly(styrene-co-maleic acid), poly(vinyl methyl ether-co-maleic acid), poly(acrylic acid-co-maleic acid), poly(ethylene-co-maleic acid) and poly(acrylic acid-co-methacrylic acid).
4. Drug delivery system of Claim 3 wherein from about 0.5 to about 20 mol % of the
resin is cross-linked.
5. Drug delivery system of Claim 4 wherein said therapeutic agent is adapted to be
absorbed by said cross-linked polyacid resin and is adapted to be released therefrom,
upon swelling of the resin, in an amount sufficient to effect therapeutic action.
6. Drug delivery system of Claim 5 wherein said therapeutic agent is a polypeptide.
7. Drug delivery system of Claim 6 wherein said polypeptide is selected from the
group consisting of insulin, growth hormones (somatotropins) and 5-ASA.
8. Method of preparing a swelling-controlled drug delivery system of Claim 1 comprising
stirring the polyacid resin in a non-polar non-solvent, adding an aqueous solution
of the therapeutic agent dropwise thereto over a time period of about one minute,
stirring until it appears that the polymer is no longer swelling, decanting the organic
layer and removing any remaining solvent.
9. Swelling-controlled drug delivery system for enteral administration of a drug comprising
a drug imbibed into a salt-free cross-linked polyacid resin, said polyacid being selected
from the group consisting of polycarboxylic acids which include one or more acid monomers
having up to about four carbon atoms per carboxylic acid radical and substituted and
unsubstituted sulfonic acid monomers.
10. Delivery system of Claim 9 wherein said polyacid is selected from the group consisting
of poly(acrylic acid), poly(methacrylic acid), poly (vinyl sulfonic acid), poly(p-styrene
sulfonic acid), poly(styrene-co-maleic acid), poly(vinyl methyl ether-co-maleic acid), poly(acrylic acid-co-maleic acid), poly(ethylene-co-maleic acid)and poly(acrylic acid-co-methacrylic acid).
11. Delivery system of Claim 9 wherein said polyacid is a polycarboxylic acid selected
from the group consisting of poly(acrylic acid), poly(methacrylic acid), poly (ethylene-co-maleic acid),poly(acrylic acid-co-methacrylic acid) and poly(vinyl methyl ether-co-maleic acid).
12. Delivery system of Claim 9 wherein said polycarboxylic acid is selected from
the group consisting of poly(acrylic acid) and poly(methacrylic acid).
13. Delivery system of Claim 12 wherein the drug is insulin.
14. Delivery system of Claim 12 wherein the drug is 5-ASA.
15. In a drug delivery system for enteral delivery of a drug, the improvement which
comprises imbibing such drug in a cross-linked polyacid resin adapted to swell minimally
in a gastric environment with no significant loss of the drug and swell extensively,
without dissolving, in an environment having a pH value greater than that of the gastric
environment with release of an effective amount of the drug.